Patient-oriented research of infections in hematopoietic cell transplantation (HCT) provides the opportunity to directly affect outcome of HCT recipients. Infections continue to be a major cause of morbidity and death after HCT. This award renewal will provide protected time for the applicant to mentor trainees in clinical research that is directly related to understanding the biology of infections after HCT. Results wil provide the basis for translation into improved management strategies. This proposal will address four areas of transplant infectious diseases: respiratory virus infections, genetics of infections, the microbiome, and human herpesvirus 6 (HHV- 6) disease manifestations. The Specific Aims are: Specific Aim 1. To investigate clinical, host and viral factors affecting advers outcomes in HCT recipients with human rhinovirus (HRV) infection, which is now the significant cause of upper and lower respiratory tract disease after HCT. In large cohort study (N=1750) we will define risk factors for progression from upper to lower respiratory tract disease (LRD). We will also examine the role of host responses (cytokines, gene expression profiles) in patients with HRV and correlate with clinical symptoms and outcomes (progression, mortality), and determine the impact of viral load, strain differences and viral shedding on disease progression, morbidity, and mortality. Specific Aim 2. To determine the impact of donor and recipient innate genetic factors on the risk and outcome of infectious complications following HCT. Using a unique cohort of 5000 donor and recipients we will perform genome-wide association studies. We will define and validate invasive aspergillosis (IA) phenotypes based on fungal antigenemia and clinical outcomes, and then define genetic variants that increase risk for IA acquisition. Using the same cohort, we will define genetic variants that increase the risk of important viral infections. Specific Aim 3. To determine how the use of antibiotics and dietary fiber intake affect gut microbiota and subsequent infections after HCT. In a prospective cohort study (N=500) we will determine the effect of antibiotic regimens and dietary fiber intake on the gut microbiota and bacterial complications, and determine if changes in gut the microbiota modulate susceptibility to viral infection and affect adaptive immunity. Specific aim 4. To conduct studies to characterize HHV-6 as a pulmonary pathogen in HCT recipients. In a cohort of patients evaluated for pneumonia by bronchoalveolar lavage (N=725), we will examine HHV-6 viral load, viral integration and cytokine expression profiles of HHV-6 LRD and characterize factors associated with overall mortality and death due to respiratory failure. These aims support an innovative approach toward POR in the field of transplant infectious diseases and the proposed studies have a high potential of advancing our knowledge of the spectrum of infectious complications, the genetic basis of diseases, and the role of microbiome.